Molecular Epidemiology of Primary CMV Infection

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DESCRIPTION (provided by applicant): Molecular techniques based on detection of genomic differences reveal that numerous CMV strains are circulating in the population. Although primary human CMV infection is traditionally believed to be caused by a single strain, previous studies of CMV strain heterogeneity have been limited mostly to organ transplant recipients. Outside this setting, isolation of multiple CMV strains has been considered proof of reinfection. Studies show that in both clinical settings and in the community, subjects (transplant patients, AIDS patients, young children in day care, sexually active persons) may be exposed to and re-infected over time with multiple CMV strains. No previous studies have determined whether initial CMV infection in healthy subjects involves multiple strains. Interest in this issue stems from our previous work in which we identified multiple CMV strains (based on UL144 and US28 genotypes) in fetuses who died in utero from congenital CMV infection. Only a single genotype was identified from cultured isolates of CMV infected live infants. Based on the literature, one would expect that these severe cases of congenital CMV infection were due to a primary maternal infection. However, the detection of multiple strains suggests that reinfection could have played a role. Whether the difference in detection is related to direct sequencing from tissue as opposed to selection of preferential isolates from culture is unclear. The goal of this application is to characterize strain heterogeneity during primary CMV infection in healthy adults through the following specific aims: 1. To determine whether primary CMV infection in healthy adults involves single strain or multiple strains based on sequence diversity in UL144, UL146 and glycoprotein B genes. 2. To determine whether CMV strains detected six to twelve months years after primary infection are different from the strain(s) detected at the time of initial infection. This exploratory study will help define the extent to which strain diversity can be used as evidence of CMV reinfection. It will likely lay the groundwork for a more extensive study (in terms of number of subjects, number of sites of viral excretion, number of genes studied) of strain diversity in primary CMV infection in the normal host. In addition this study will have significant implications for vaccine development and understanding how natural CMV infection leads to broad immunity to the virus. PHS 398/2590 (Rev. 05/01) Page 2 Continuation Format Page CMV (cytomegalovirus) infection is the most common infection transmitted from mothers to newborns, affecting 1 percent of newborns worldwide. There are several variations in the genetic makeup of the virus, and the professional term for those is viral strains. The goal of this application is to determine whether acute CMV infection is caused by a single strain or multiple strains, as determined using genetic sequencing techniques on a variety of bodily fluids. This application will improve our understanding of acute CMV infection and will open new research directions in vaccine development. .